title: Dynamics of cancer cell subpopulations in primary and metastatic colorectal tumors.
abstract: Intratumor heterogeneity-heterogeneity of cancer cells within a single tumor-is considered one of the most problematic factors of treatment. Genetic heterogeneity, such as in somatic mutations and chromosome aberrations, is a common characteristic of human solid tumors and is probably the basis of biological heterogeneity. Using mutations in APC, TP53 and KRAS as markers to identify distinct colorectal cancer subpopulations, we analyzed a total of 42 primary colorectal cancer tissues and six paired liver metastases with multipoint microsampling, which enabled analysis of mutation patterns and allelic imbalances with a resolution of 0.01 mm(2) (about 200 cells). There was usually more than one subpopulation in each primary tumor. Only two of 15 (13.3%) cases with three gene mutations and eight of 27 (29.6%) cases with two gene mutations had a single subpopulation. Cells with mutations in all of the examined genes usually constituted the major population. Multipoint microsampling of six primary and metastatic tumor pairs revealed that the majority of discrepancies in mutation patterns found with the bulk tissue analysis were due to loss of subpopulations in the metastatic tissues. In addition, multipoint microsampling uncovered substantial changes in subpopulations that were not detected with bulk tissue analysis. Specifically, the proportion of KRAS mutation-negative subpopulations increased in the metastatic tumors of four cases. Because KRAS mutation status is linked to cetuximab/panitumumab efficacy, subpopulation dynamics could lead to differences in response to cetuximab/panitumumab in primary versus metastatic tumors.
authors.affiliation: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan.
authors.forename: Teodora Evgenieva
authors.initials: TE
authors.lastname: Goranova
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohue
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Shimoharu
authors.forename: Kikuya
authors.initials: K
authors.lastname: Kato
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D005838:Genotype; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins